2d
ISAP Discussion Workshop (Wiks Castle, Uppsala, Sweden, June 10th,
1999)
The role of
Pharmacokinetics / Pharmacodynamic (PK/PD) information in the clinical
development of antibiotics: A Scientific/Regulatory Workshop
A workshop co-sponsored
by ISAP and MPA (Swedish
Medical Product Agency) acting on behalf of the CPMP (Committee for
Propriety Medicinal Products) of EMEA (European
Agency for the Evaluation of Medicinal Products)
Organizers:O. Cars (ISAP,
Upsala, Sweden) and B. Odlind (MPA/CPMP/EMEA, Uppsala, Sweden)
The slides
presented by some of the speakers at
this workshop are available on this site as "Web slide shows" (more slides
will be presented soon). To view them, click on the title of the
lectures if underlined and in blue
(more slides will be available in near future). The content of these
slides reflect the views of their authors and should not be taken as being
endorsed by ISAP or FDA. They are shown for information purposes
only and cannot be reproduced or used for any form of presentations
without the autorization of their author, ISAP and EMEA/MPA.
Please, contact the ISAP Webmaster
for further information.
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Wecome and introduction (B.
Odlind, MPA, Uppsala, Sweden)
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The
problem (O. Cars, ISAP & Akdemiska Sjukhuset,
Uppsala, Sweden)
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Current
Regulatory positions(B: Aronsson, CPMP, EMEA,
London, UK)
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The
techniques: in vitro models (E. Löwdin,
MPA, Uppsala, Sweden)
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The
techniques: in vivo models (W.A. Craig,
ISAP & University of Wisconsin, Madison, WI)
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The
techniques: PK/PD analysis [part 1] (M. Gårdmark,
MPA, Uppsala, Sweden)
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The
techniques: PK/PD analysis [part 2] (J. Wade,
MPA, Uppsala, Sweden)
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Time
for a change: my personnal view (P.M. Tulkens,
ISAP & Université Catholique de Louvain, Brussels, Belgium)
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Discussion (preclinical development;
clinical development; new needs for registration)
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Pre-meeting
Introduction
The meeting
should serve to construct the scientific basis for Proposals to be presented
by the European Working Party (EWP) of the Committee for Proprietary
Medicinal Products (CPMP) to the European
Agency for the Evaluation of Medicinal Products (EMEA) for considering
the development of a 'Guidelines for the choice of dose and dosing regimens
based on pharamcokinetic and pharmacodynamic data in relation to outcome
and the development of resistance'.
There
is indeed convincing evidence that the dose, dosing interval and clinical
efficacy of an antibacterial can be related to various pharmacokinetic
(PK) and pharmacodynamic (PD) parameters. Similarly, PK and PD data
can be used to assist in a rational approach to setting breakpoints between
susceptible and resistant bacteria (currently, many national bodies differ
in their approach and different breakpoints exist in the vaious countries
of the European Union [EU]). Evidences to hand
suggest that the ratio of area-under-the-serum-concentration-time-curve
to the MIC is the predictor of efficacy for fluoroquinolones; for beta-lactams,
the parameter is the time the serum concentration exceeds the MIC, and
for aminoglycosides the ratio of Cmax to MIC is relevant to outcome.
Recent information also indicates that attention to proper dosing can minimize
the mergence of resistance.
Application
for Maketing Authorization for new antimicrobials agenst should provide
PD and PK data relevant to the agent and the indications (i.e. the sites
of infection) sought. A more rational approach to the selection,
design and interpretation of these studies has the potential to provide
a firm base for the latter phase of clinical development and, particularly,
for the conduct of the major trials of clinical safety and efficacy.
Such data would also serve as the basis for a more scientific selection
of the preliminary susceptibility test breakpoints to be taken forward
into Phase III.
On this
basis, the aims of the meeting are to provide guidance to the Pharmaceutical
Industry on:
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the scope of human pharmacokinetics
pertinent to the antibacterials;
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the scope of pharmacodynamic
investigations for differing classes of antimicrobials for both in vitro
and in vivo models of infection;
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the appropriate design of clinical
trials to validate PK/PD that has been determined in pre-clinical studies;
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to develop appropriate PK/PD
data to minimize the development of bacterial resistance, and more specifically:
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to select a preliminary beakpoint
between susceptible and resistant populations of bacteria based on PK and
PD data;
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to confirm the validity of that
breakpoint from clinical trial experience.
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Credits:
last significant update: June 12, 1999,
1999
